Potential pathogenic role of soluble receptor activator of nuclear factor-ĸB ligand and osteoprotegerin in patients with pulmonary arterial hypertension

INTRODUCTION Inflammation plays a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Soluble receptor activator of nuclear factor-ĸB ligand (sRANKL) and osteoprotegerin (OPG) are tumor necrosis factor α family members of immunomodulatory activity.

OBJECTIVES The aim of the study was to evaluate sRANKL and OPG concentrations in patients with PAH as potential factors contributing to the development of the disease.

PATIENTS AND METHODS We studied 26 patients with PAH, 31 volunteers, and 24 stable patients with chronic systolic left ventricular heart failure (LVHF) without pulmonary hypertension. The PAH group was followed up for 6 months for clinical deterioration or death.

RESULTS sRANKL levels were higher in the PAH group compared with controls and the LVHF group (5.6 [interquartile range, 3.9–7.9) vs. 2.0 [0.9–4.4] pmol/l; P = 0.0001, and 2.4 [1.3–4.2] pmol/l; P = 0.001, respectively). OPG levels were higher in PAH patients compared with controls (4.07 ±1.9 vs. 3.27 ±0.95 pmol/l; P = 0.048). We found significant correlations between sRANKL levels and parameters of ventilatory efficiency during exercise in the PAH group. OPG levels correlated with brain natriuretic peptide levels and with invasive hemodynamic parameters. Patients with clinical deterioration during 6-month follow-up (n = 9) showed higher baseline OPG levels compared with stable patients (n = 17, 5.09 ±2.6 vs. 3.52 ±1.19 pmol/l; P = 0.043). In the univariate analysis, the elevated OPG concentration at baseline was associated with an increased risk and earlier occurrence of clinical deterioration (hazard ratio, 1.43; 95% confidence interval, 1.06–1.9; P = 0.017).

CONCLUSIONS Concentrations of sRANKL and OPG are elevated in patients with PAH and are associated with indicators of disease severity and prognosis. sRANKL is a better discriminant between PAH and LVHF than OPG. The baseline OPG concentration is significantly associated with adverse outcomes in patients with PAH.